The eukaryotic genome is organized as a highly complex nucleoprotein structure called chromatin, the unit of which is the nucleosome. The nucleosome is composed of two copies each of four different histones, H3, H2B, H2A, and H4, constituting a scaffold, which is wrapped around by 146 base pairs of DNA. Therefore, for any process that requires access to the DNA (e.g. transcription, replication, recombination, and repair), the chromatin needs to be opened by the remodeling systems. There are two different biochemical processes to modify chromatin structure, namely the covalent modifications of histone tails and the ATP-dependent chromatin remodeling. Among the several covalent modifications of histones known, the reversible acetylation of key lysine residues in histones holds a pivotal position in transcriptional regulation. Acetylation of histones is a distinctive feature of the transcriptionally active genes, whereas deacetylation indicates the repressed state of a gene. A balance between the acetylation and deacetylation states of histones regulates transcription. Dysfunction of the enzymes involved in these events, the histone acetyltransferases (HATs) and histone deacetylases (HDACs), is often associated with the manifestation of cancer. These enzymes thus become potential new targets for antineoplastic therapy.
A wide repertoire of transcriptional co-activator proteins is now recognized to possess histone acetyltransferase activity. These include p300/CBP-associated factor (PCAF), which is similar to GCN5, nuclear hormone receptor cofactors such as steroid receptor cofactor 1 (SRC1) and activator of thyroid and retinoid receptor (ACTR) and the multifunctional p300/CBP. The p300/CBP is a global transcriptional coactivator, which plays a critical role in a variety of cellular process including cell cycle control, differentiation, and apoptosis. Mutations in p300/CBP are associated with different human cancers and other human diseases. It is one of the most potent histone acetyltransferases, which can acetylate all four-core histones within nucleosomes as well as free histone forms. The HAT activity of p300 is regulated by several other factors. For example, the viral oncoprotein E1A binds to p300 and inhibits its activity, whereas phosphorylation of CBP by cyclin E/Cdk2 kinase activates its HAT activity. During the process of transcription, p300 is recruited on to the chromatin template through the direct interaction with the activator and enhances the transcription by acetylation of promoter proximal nucleosomal histones.
Although significant progress has been made in the field of histone deacetylase inhibitors as antineoplastic therapeutics, and some of the compounds are already in human trials the reports of HAT inhibitors/activators are scanty. Prior to the molecular characterization of HAT enzymes, several polyamine-CoA conjugates were found to block HAT activity in cell extracts. However, the target enzyme(s) for these conjugates was not known. Recently, two peptide-CoA conjugates, namely Lysyl CoA (Lys-CoA) and H3-CoA-20, were synthesized that specifically inhibit the HAT activity of p300 and PCAF, respectively. Thus, there is an urgent medical need to identify new drugs having modulating activity (inhibitors/activators) towards histone acetyltransferases which can be used to treat diseases in which histone acetyltransferase play an important role treatment of diseases due to defects in gene regulation predominantly cancer.
In accordance with the present invention, there is therefore provided the use of a compound of general formula I for activator molecules of histone acetyltransferases and the use of a compound of general formula II for inhibitor molecules of histone acetyltransferases.